Small Cell Lung Carcinoma (SCLC) is a neuroendocrine subtype of lung cancer. The 5-year survival of SCLC patients is dismal, in large part due to the very transient effects of chemotherapy and the absence of targeted therapies against this cancer type. The world's population continues to increase and the number of smokers quickly follows. Thus, SCLC, which kills more than 200,000 patients every year - most of them heavy smokers - will continue to be a major health issue in the decades to come. Our overarching goal is to gain a better understanding of the mechanisms underlying SCLC development to aid in the development of novel therapeutic strategies in the future. Notch signaling controls cell fate and differentiation in multiple lineages. Interestingly, the Notch pathway is also implicated in various cancer types, and an increasing number of therapeutic tools are being developed to target this pathway in tumor cells. However, the role of Notch signaling is context-dependent, acting as an oncogene or a tumor suppressor in different cell lineages. Thus, it is critical to thoroughly investigate the mode of action of the Notch pathway in specific contexts before any clinical strategy may be safely implemented. Accumulating evidence suggests that active Notch signaling may play a tumor suppressive role in SCLC. In part, these effects may be due to the inhibition of neuroendocrine differentiation by Notch, similar to what is seen during lung development and in the adult lung epithelium in response to injury. However, the exact role of the Notch pathway in SCLC development and response to therapy has not been determined. We will use a combination of mouse genetics, primary mouse and human cancer cells, and molecular, biochemical, and genomics tools to address these key questions. Specifically, we have made the intriguing observation that a contingent of Notch pathway-active tumor cells is naturally present in SCLC tumors, defining a new level of tumor heterogeneity in SCLC. We will investigate how these Notch pathway-active tumor cells interact with the rest of the tumor, including possible tumor-promoting roles for these cells. We have also found that ectopic activation of Notch in all tumor cells initially suppresses the growth of SCLC but, in a second phase, reprograms SCLC neuroendocrine tumor cells towards a non-neuroendocrine state in which Notch becomes oncogenic. Building upon these data, we will determine the optimal conditions for Notch activation to inhibit SCLC cells without triggering this oncogenic switch. Finally, we will use advanced molecular and genomic tools to elucidate the molecular mechanisms by which Notch activation reprograms SCLC cells to a non-neuroendocrine fate. These experiments will provide novel insights into the basic mechanisms of Notch signaling and may help identify novel strategies for targeted therapy directed at SCLC, the most lethal form of lung cancer.